Cryopyrin-associated periodic syndromes (CAPS) are a family of rare autoinflammatory diseases of which neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype. NOMID is characterized by NLRP3 activating mutations resulting in excessive interleukin- 1?IL-1?and IL-18 production associated with recurrent fever, rash, skeletal lesions, chronic meningitis, seizures, deafness and mental impairment. Consistent with IL-1? central role in these disorders, protein-based anti-IL-1drugs such as anakinra have demonstrated efficacy in the treatment of NOMID. Unfortunately, these drugs suffer from high price, the requirement for parenteral administration, the potential for development of resistance and the lack of efficacy against skeletal lesions. These shortcomings provide a strong rationale for the development of a safe, more effective and affordable oral inhibitor of IL-1?o treat this disease. IL-1?iosynthesis is regulated by p38 an JNK mitogen-activated protein kinases and I?B kinase and the activation of each is controlled by transforming growth factor-?ctivated kinase 1 (TAK1). TAK1 is critical not only in the biosynthesis of IL-1?IL-18 and NLRP3, but also in IL-1?ignaling, thereby positioning this kinase as a drug target for the treatment of CAPS. In this SBIR Phase I application, Confluence Life Sciences (CLS) proposes to develop the first proprietary TAK1 inhibitor drug candidate for the treatment of CAPS. CLS has developed an innovative kinase drug discovery platform (KINect) that exploits our proprietary kinase inhibitor library in the context of structure-based drug design (SBDD) to rapidly identify and develop active, drug-like chemical cores into drug candidates. Using this approach CLS has recently identified a set of potent and proprietary lead TAK1 inhibitor compounds. From this starting point, CLS proposes to develop TAK1 drug candidates focusing on the following specific aims: (1) Optimize the pharmaceutical properties of two TAK1 inhibitor lead series and determine their efficacy in blocking IL-1?IL-18 and NLRP3 biosynthesis as well as IL-1?ignaling in murine CAPS bone marrow-derived macrophages (BMDM) and peripheral blood mononuclear cells (PBMC) from CAPS patients and (2) Determine the efficacy of TAK1 drug candidates in a murine NOMID model. SBIR phase 2 studies will focus on product development and advancement of the program through human Phase 1 clinical evaluation in CAPS patients. Supporting studies will include regulatory toxicology, pharmacokinetics and drug product synthesis. The resulting product will be of great interest to drug companies and we anticipate a co-development partnership license. Commercial deals for assets at this stage are highly precedented in the industry and typically total >$100M. Given the great need for an effective therapeutic for CAPS, the development of a safe TAK1 inhibitor drug candidate will have a major medical impact.